Type 3 iodothyronine deiodinase (D3) is the main physiologic inactivator of thyroid hormone, catalyzing the inner-ring deiodination of thyroxine (T4) to reverse triiodothyronine (rT3) and triiodothyronine (T3) to 3,3'- diiodothyronine (T2), both of which are biologically inactive. In humans, D3 is highly expressed in the fetus and then, upon birth, rapidly falls to undetectable levels in all but a few tissues (the central nervous system and the skin). High D3 expression has been documented in several tumor types and we have shown that patients with large DS-expressing vascular anomalies or fibrous tumors can develop severe hypothyroidism due to the rapid destruction of circulating thyroid hormone, a condition we have termed "consumptive hypothyroidism." Because of this expression pattern, D3 is often described as an oncofetal protein, but recent data indicate that it is also reactivated in benign postnatal tissues during shock, cardiac failure, and chronic inflammation. While consumptive hypothyroidism illustrates D3's potency as a modulator of thyroid status, the reactivation of D3 in these nonmalignant tissues implies that a reduction in the local concentration of T3 may be a critical, previously-unrecognized component of the normal tissue response to injury. The molecular mechanisms which regulate D3's expression and whether D3 activity in postnatal tissues is adaptive or maladaptive are largely unknown. The goals of this proposal are to identify mechanisms of D3 induction in injury and to investigate the biological relevance of the resultant changes in local thyroid status. Mechanisms of D3 induction will be studied in vitro using recently identified D3-expressing cell cultures. In addition, we will use an in vivo animal model to study the impact of D3 expression on both local thyroid hormone action and the modulation of systemic thyroid status.